15-methyl and ethyl-15(r)-pgf2alpha

ABSTRACT

PROSTAGLANDIN F2A-TYPE 15-EPIMERIC COMPOUNDS WITH A METHYL OR AN ETHYL SUBSTITUENT AT C-15. THESE ARE USEFUL FOR THE SAME PHARMACOLOGICAL PURPOSES AS THE UNSUBSTITUTED PROSTAGLANDINS.

United States Patent-O US. Cl. 260- 514 D I l 3 Claims ABSTRACT OF THEDISCLOSURE Prostaglandin'F -type -epimeric compounds with a methyl or anethyl substituent at'C-ISQThese are useful for the same pharmacologicalstituted'prostaglandins.

CROSS-REFERENCE. TO RELATED APPLICATIONS This application is acontinuation-in-part of my copending application Ser. No. 34,518 filedPat. No. 3,728,382.

DESCRIPTION OF THE INVENTION, This invention relates to novelcompositions of matter,

purposes as the unsub- J May 4, 1970 now to novel methods for producingthose, and to novel chemical intermediates useful in those processes. Inparticular, this invention relates to novel derivatives of prostanoicacid which has the following structure and atom numbering: v

Various derivatives of prostanoic acid are known in the art. These arecalled prostaglandins. See, for example,

Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and

references cited therein. For example, prostaglandin E (PGE has thefollowing structure:

1 COOH JvM/V HO H Prostaglandin E (PGE has the following structure:

(III) I 3,804,890 Patented Apr. 16, 1974 Dihydroprostalandin E(dihydro-PGE has the following structure:

Prostaglandins with a secondary alpha or. beta hydroxy in place of thering oxo of the prostaglandins E are also known. These are calledprotaglandins F. For example, prostaglandin F (PGF has the followingstructure:

OH (VII) Prostaglandins F, and F, corresponding to PGE PGE anddihydro-PGE are also known.

In Formulas II and VH, broken line attachments to the cyclopentane ringindicate substituents in alpha configuration, i.e., below the plane ofthe cyclopentane ring. Heavy solid line attachments to the cyclopentanering indicate substituents in beta configuration, i.e., above the planeof the cyclopentane ring. The side-chain hydroxy at C- 15 in Formulas IIto VII is'in S configuration. See Nature, 212, 38 (1966) for discussionof the stereoche'mistry of the prostaglandins.

Molecules of the ,.known prostaglandin's each have several centers ofasymmetry, .and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) form, i.e., thedextrorotatory and levorotatory forms. As drawn, Formulas II to VIIeach-represent the particular optically active form ofi theprostaglandin which is' obtained from certain mam'm'a- Han tissues, forexample, sheep vesicular" glands, swine lung, or human seminal plasma,or by carbonyl and/or double Ibond reduction of a prostaglandin soobtained. See, for example, Bergstrom et al., cited above. The mirrorimage of each of FormulasII to VII would represent the ,other enantiomerof that prostaglandin. The v racemic form of a prostaglandin wouldcontain numbers Q of both enantiomeric molecules, and one of FormulasvII to VII and the mirror image of that formula would both be needed torepresent correctlythe corresponding race-. i :mic prostaglandin. Forconvenience hereinafter, use of and dihydro-PGF will mean the opticallyactive form, I

of that prostaglandin with the same absolute configuration as PGEobtained from mammalian tissues. When reference to the racemic form ofone of those prostaglandins is intended, the word racemic will precedethe prostaglandin name, thus, racemic PGE or racemic 3 Each of the novelprostanoic acid derivatives of this invention is encompassed by one ofthe following formulas or by the combination of that formula and itsmirror image:

(VIII) In-Formulas VIII to XIII, R is hydrogen, alkyl of one to 8 carbonatoms, inclusive, or a pharmacologically acceptable cation, R is methylor ethyl, and X is oxo, alpha hydroxy, or beta hydroxy, i.e.=0,

or: OK

In Formulas VIII, X, and XH, the configuration of the hydroxy at (3-15is S as in the known prostaglandins of Formulas II to VII. In FormulasIX, XI, and XIII, the hydroxy at C-15 is in the unnatural Rconfiguration. See J. Chem. Education, 41, 116 (1964), for discussion ofS and R configurations.

A significant characteristic of all of the known prostaglandins is thesecondary hydroxy group at -15, i.e., the atom grouping Prostaglandinsobtained rrom animal tissues always contain that atom grouping. Instriking contrast, each of the novel prostanoic acid derivatives of thisinvention has a tertiary hydroxy group at 0-15, i.e., the atom groupingor the corresponding R configuration grouping wherein R is methyl orethyl. Thus, these novel prostanoic acid derivatives may conveniently bedesignated IS-methyl-prostaglandins or l5-ethyl-prostaglandins, e.g.,15-methyl-PGE IS-ethyl-PGF and 15-methyl-l5(R)- PGF As in the case ofFormulas II to VII, Formulas VIII to XIII are each intended to representoptically active prostanoic acid derivatives having, except for thehydroxy at C-9 or C-15 in certain compounds, the same absoluteconfiguration as PGE obtained from mammalian tissues. In addition, thenovel prostanonic acid derivatives of this invention also include thecorresponding racemic compounds. One of Formulas VIII-XIII, inclusive,plus the mirror image of that formula are necessary in combination todescribe a racemic compound. For convenience hereinafter, when the wordracemic precedes the name of one of the novel prostanoic acidderivatives of this invention, the intent is to designate a racemiccompound represented by the combination of the appropriate Formulas VIIIto XIII and the mirror image of that formula. When the word racemic doesnot precede the compound name, the intent is to designate an opticallyactive compound represented only by the appropriate Formulas VIII toXIII and with the same absolute configuration as PGE obtained fromanimal tissues.

PGE PGE PGE dihydro-PGE and the corresponding PGF, and PGE, compounds,and their esters and pharmacologically acceptable salts are extremelypotent in causing various biological responses. For that reason, thesecompounds are useful for pharmacological purposes. See, for example,Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references citedtherein. A few of those biological responses are systemic arterial bloodpressure lowering in the case of the PGE and PGF, compounds as measured,for example, in anesthetized (pontobarbital sodium) pentolinium-treatedrats with indwelling aortic and right heart cannulas; pressor activity,similarly measured, for the PGF,, compounds; stimulation of smoothmuscle as shown, for example, by tests on strips of guinea pig ileum,rabbit duodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepinephrineinduced mobilization of free fatty acids or inhibition of thespontaneous release of glycerol from isolated rat fat pads; inhibitionof gastric secretion in the case of the PGE compounds as shown in dogswith secretion stimulated by food or histamine infusion; activity on thecentral nervous system; decrease of blood platelet adhesiveness as shownby platelet-to-glass adhesiveness, and inhibition of blood plateletaggregation and thrombus formation induced by various physical stimuli,e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP,serotonin, thrombin, and collagen; and in the case of the PGE compounds,stimulation of epidermal proliferation and keratinization as shown whenapplied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about g. to about 10mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certainuseful animals, e.g., dogs and pigs, to reduce and control excessivegastric secretion, thereby reducing or avoiding gastrointestinal ulcerformation, and accelerating the healing of such ulcers already presentin the gastrointestinal tract. For this purpose, the compounds areinjected or infused intravenously, subcutaneously, or intramuscularly inan infusion dose range about 0.1 g. to about 500 g. per kg. of bodyweight per minute, or in a total daily dose by injection or infusion inthe range about 0.1 to about 20 mg. per kg. of body weight per day, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

The PGE, PGF and PGF, compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arterio sclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF,, and PGF, compounds are especially useful as additives toblood, blood products, blood substitutes, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood Vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout .001 to 10mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the rangeabout 0.01to 6 about 50 g. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE and PGF, compounds are useful as hypotensive agents to reduceblood pressure in mammals, including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 to about g. per kg. of body weight per minute, or in single ormultiple doses of about 25 to 500 g. per kg. of body weight total perday.

The PGE, PGF,,, and PGF, compounds are useful in place of oxytocin toinduce labor in pregnant female animals, including man, cows, sheep, andpigs, at or near term, or in pregnant animals with intrauterine death ofthe fetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose 0.01 to 50 pg. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more Weeks post-mature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started.

The PGF,, PGF,,, and PGE compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Forthat purpose, *PGE or PGF for example, is administered systemically,e.g., intravenously, subcutaneously, and intravaginally, at a dose levelin the range 0.001 mg. to about 20 mg. per kg. of body weight of thefemale mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thenext expected time of menses or just prior to that time. Additionally,expulsion of an embryo or fetus is accomplished by similaradministration of the compound during the first third of the normalmammalian gestation period.

\As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyrodism.

The novel 15-methyl and 15-ethyl prostaglandin analogs encompassed byFormulas VIII to XIII, the corresponding R and S 15-methyl and 15-ethylPGE :PGF and PGF compounds, and also the corresponding racemic analogseach cause the same biological responses described above for thecorresponding known prostaglandins. Each of these IS-methyl and 15-ethylcompounds is accordingly useful for the above-described pharmacologicalpurposes, and is used for those purposes as described above. However,each of these l5-methyl and 15-ethyl prostaglandin analogs issurprisingly and unexpectedly more useful than the corresponding knownprostaglandin for at least one of the pharmacological purposes describedabove because for that purpose the analog is more potent and has asubstantially longer duration of activity. For that reason, fewer andsmaller doses of these prostaglandin analogs are needed to attain thedesired pharmacological results.

The novel PGE-type, PGF -type, and PGF -type analogs encompassed byFormulas VIII to XIII, the corresponding R and S 'PGE PGF and PGFanalogs, and also the corresponding racemic analogs are used asdescribed above in free acid form, in alkyl ester form, or in.pharmacologically acceptable salt form. When the ester form is used,any alkyl ester can be used wherein the alkyl moiety contains one to 8carbon atoms, inclusive, i.e.,

methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,

and isomeric forms thereof. However, it is preferred that the ester bealkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimental animal system.

Pharmacologically acceptable salts of these prostaglandin analogs usefulfor the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmalocogically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, fl-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,Z-methylpyrrolidine, 1,4- dimethylpiperazine, Z-methylpiperidine, andthe like, as Well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-l-pr0- panol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the prostaglandin analogs are administered invarious ways for various purposes; e.g., intravenously, intramuscularly,subcutaneously, orally, intravaginally, rectally, buccally,sublingually, topically, and in the form of sterile implants forprolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility to use the free acid form or thepharmacologically acceptable salt form. For subcutaneous orintramuscular injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or non-aqueous media are used. Tablets,capsules, and liquid preparations such as syrups, elixirs, and simplesolutions, with the usual pharmaceutical carriers are used for oral orsublingual administration. For rectal or vaginal administration,suppositories, tampons, ring devices, and preparations adapted togenerate sprays or foams or to be used for lavage, all prepared asknownin the art, are used. For tissue implants, a sterile tablet or siliconerubber capsule or other object containing or impregnated with thesubstance is used.

The novel PGE-type acids and alkyl esters of Formulas VIII to XIIIwherein X is =0, and also the corresponding R and S PGE -type acids andalkyl esters are prepared by oxidation of the corresponding PGF -type orPGF -type acids and alkyl esters. For this purpose, an oxidizing agentis used which selectively oxidizes secondary hydroxy groups to carbonylgroups in the presence of carbon-carbon double bonds. Thesetransformation are shown in Chart A, wherein the formulas as drawnrepresent optically active compounds. When the same process steps areapplied to the corresponding racemic starting materials consisting ofthe optically active compounds as depicted and the mirror imagesthereof, those process steps yield the corresponding racemicintermediates or racemic prostaglandin analogs. Likewise, thecorresponding IS-epimeric starting materials of either the opticallyactive compounds or their racemates yield the corresponding 15-epimericproducts. Also in Chart A, R is methyl or ethyl, R is hydrogen or alkylof one to 8 carbon atoms, inclusive, X and Y are both CH CH or X istrans- CH=CH and Y is CH CH or cis-CH=CH-, and indicates attachment ofhydroxy to the ring in alpha or beta configuration.

For the transformations of Chart A, the beta isomers of reactants XIVand XVI are preferred starting materials, although the correspondingalpha isomers are also useful for this purpose.

Oxidation reagents useful for the transformations set forth in Chart Aare known to the art. An especially useful reagent for this purpose isthe Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39(1946). Acetone is a suitable diluent for this purpose, and a slightexcess beyond the amount necessary to oxidize one of the secondaryhydroxy groups of the Formula XIV or XVI reactant is used. Reactiontemperatures at least as low as about 0 C. should be used. Preferredreaction temperatures are in the range -10 to 50 C. The oxidationproceeds rapidly and is usually complete in about 5 to about 20 minutes.The excess oxidant is destroyed, for example, by addition of a loweralkanol, advantageously, isopropyl alcohol, and the Formula XV or XVIIPGE-type product is isolated by conventional methods.

CHART A HO O Examples of other oxidation reagents useful for the Chart Atransformations are silver carbonate on Celite (Chem. Commun. 1102(1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters3363 (1968),

I. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351 (1962)),mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (I. Am.Chem. Soc. 89, 5505 (1967) and mixtures of dicyclohexylcarbodiimide anddimethyl sulfoxide, (J. Am. Chem. Soc. 87, 5661 (1965)).

The novel PGF -type and PGF -type acids and esters of Formulas VIII toXIII wherein X is on on and also the corresponding PGF -type and PGF-type acids and alkyl esters are prepared by the sequence oftransformations shown in Charts B and C, wherein the formulas as drawnrepresent optically active compounds. The corresponding racemic startingmaterials yield the corresponding racemic intermediates or racemicprostaglandin analogs, applying the process steps of Charts B and C.Also in Charts B and C, R is methyl or ethyl, R is hydrogen or alkyl ofone to 8 carbon atoms, inclusive, X and Y are both -CH CH or Xtrans-CH=CH- and Y is CH CH or cis-CH=CH-, and indicates attachment ofhydroxy to the ring in alpha or beta configuration. Also in Charts B andC, A is alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2fluoro, chloro or alkyl of one to 4 carbon atoms, inclusive, and R isalkyl of one to 8 carbon atoms, inclusive, or Si(A) wherein A is asdefined above.

R2 OH (XXII) CHART C I o 0 0 E4 E6 H OH (XXIII) 1 (oxidation) I no AXXIV l (silylatlon) (A)aSi-O e 0 o R; A), s1 o h XXV l R2MgX1(hydrolysis) I HO R2 OH XXVI) (XXVII) The various A of a --Si(A) moietyare alike or difierent. For example, an -Si(A) can be trimethylsilyl,dimethylphenylsilyl, or methylphenylbenzylsilyl. Examples of alkyl ofone to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. Examples of aralkyl of 7 to12 carbon atoms, inclusive, are benzyl, phenethyl, a-phenylethyl, 3-

phenylpropyl, a-naphthylmethyl, and 2-(B-naphthyl)- ethyl. Examples ofphenyl substituted with one or 2 fluoro, chloro, or alkyl of one of 4carbon atoms, inclusive, are p-chlorophenyl, m-fluorophenyl, o-tolyl,2,4-dichlorophenyl, p-tert-butylphenyl, 4 chloro 2 methylphenyl and2,4-dicl1loro-3-methylphenyl.

In Charts B and C, the final PGF, and PGF, products are thoseencompassed by Formulas XXI+XXII and XXVI+XXVII, respectively.

The initial optically active reactants of Formulas XVIII and XXIII inCharts B and C, i.e., PGF PGF PGF PGF PGF PGF dihydro-PGF anddihydro-PGR, and their alkyl esters are known in the art or are preparedby methods known in the art. See, for example, Bergstrom et al., citedabove, US. Pat. No. 3,069,322, and British specification No. 1,040,544.The initial racemic reactants of Formula XVIII in Chart B, i.e., racemicPGF racemic PGF racemic PGF racemic PGF racemic PGF and racemic PGF andtheir alkyl esters are known in the art or are prepared by methods knownin the art. See, for example, Just et al., J. Am. Chem. soc. 91, 534(1969), Corey et al., J. Am. Chem. Soc. 90, 3245 (1968), Schneider etal., Chemical Communications (Great Britain), 304 (1969), and Axen,Chemical Communications, 602 (1970).

Racemic dihydro-PGF and racemic dihydro-PGF and their esters areprepared by catalytic hydrogenation of the corresponding racemic PGF orPGF and PGF or PGF compounds, respectively, for example, in the presenceof 5% palladium-on-charcoal catalyst in ethyl acetate solution at 25 C.and one atmosphere pressure of hydrogen.

The known acids and esters of Formulas XVIII and XXIH are transformed tothe corresponding intermediate l5-oxo acids and esters of Formulas XIXand XXIV, respectively, by oxidation with reagents such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganese dioxide,or nickel peroxide (see Fieser et al., Reagents for Organic Synthesis,John Wiley and Sons, Inc., New York, N.Y., pp. 215, 637, and 731).Altematively, and especially for the Formula XVIII reactants wherein Xand Y are -CH CH these oxidations are carried out by oxygenation in thepresence of the hydroxyprostaglandin dehydrogenase of swine lung (seeArkiv for Kemi 25, 293 (1966)). These reagents are used according toprocedures known in the art. See, for example, J. Biol. Chem. 239, 4097(1964).

Referring again to Charts B and C, the intermediate compounds ofFormulas XIX and XXIV are transformed to silyl derivatives of FormulasXX and XXV, respectively, by procedures known in the art. See, forexample, Pierece, Silylation of Organic Compounds," Pierce Chemical Co.,Rockford, Ill. (1968). Both hydroxy groups of the Formula XIX or XXIVreactants are thereby transformed to -O $i(A) moieties wherein A is asdefined above, and sufficient of the silylating agent is used for thatpurpose according to known procedures. When R in the Formula XIX or XXIVintermediate is hydrogen, the -COOH moiety thereby defined issimultaneously transformed to COO-Si(A) additional silylating agentbeing used for this purpose. This latter transformation is aided byexcess silylating agent and prolonged treatment. When R in Formulas XD(and XXIV is alkyl, then R in Formulas XX and XXV will also be alkyl. Thenecessary silylating agents for these transformations are known in theart or are prepared by methods known in the art. See, for example, Post,Silicones and Other Organic Silicon Compounds, Reinhold PublishingCorp., New York, N.Y. (1949).

Referring again to Charts B and C, the intermediate silyl compounds ofFormulas XX and XXV are transformed to the final compounds of FormulaXXI+XXII and XXVI-I-XXVJII, respectively, by first reacting the silylcompound with Grignard reagent of the formula R MgX wherein R is methylor ethyl, and X is chloro,

bromo, or iodo. For this purpose, it is preferred that X be bromo. Thisreaction is carried out by the usual procedure for Grignard reactions,using diethyl ether as a reaction solvent and saturated aqueous ammoniumchloride solution to hydrolyze the Grignard complex. The resultingdisilyl or trisilyl tertiary alcohol is then hydrolyzed with water toremove the silyl groups. For this purpose, it is advantageous to use amixture of water and sufficient of a water-miscible solvent, e.g.,ethanol to give a homogeneous reaction mixture. The hydrolysis isusually complete in 2 to 6 hours at 25 C., and is preferably carried outin an atmosphere of an inert gas, e.g., nitrogen or argon.

The mixture of 15-8 and 15-R isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 154 and 15-R isomersis more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to esterify themixture of acids as described below, separate the two esters, and then,if desired, saponify the esters by procedures known in the art forsaponification of prostaglandins F.

Although Formulas XXI and XXII compounds wherein X and Y are both CH CHare produced according to the processes of Chart B, it is preferred toproduce those novel dihydro-PGF analogs by hydrogenation of one of thecorresponding unsaturated compounds, i.e., a compound of Formula XX I orXXII wherein X is trans-CH=CH- and Y is --CH CH or cis-CH=CH or acompound of Formula XXVI or XXVII. This hydrogenation is advantageouslycarried out catalytically, for example, in the presence of a 5%palladium-on-charcoal catalyst in ethyl acetate solution at 25 C. andone atmosphere pressure of hydrogen.

As discussed above, the processes of Charts A, B and C lead either toacids (R is hydrogen) or to alkyl esters (R is alkyl of one to 8 carbonatoms, inclusive). When a Forrmula XXI, XXII, XXVI, )OCVH PGF-type acidor a Formula XV or XVII PGE-type acid (Chart A) has been prepared and analkyl ester is desired, esterification is advantageously accomplished byinteraction of the acid with the appropriate diazohydrocarbon. Forexample, when diazomethane is used, the methyl esters are produced.Similar use of diazoethane, diazobutane, and 1-diazo-2-ethylhexane, forexample, gives the ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed .by evaporation, and the ester purified ifdesired by conventional methods, preferably by chromatography. It ispreferred that contact of the acid reactants with the diazohydrocarbonbe no longer than necessary to effect the desired esterification,preferably about one to about ten minutes, to avoid undesired molecularchanges. Diazohydrocarbons are known in the art or can be prepared bymethods known in the art. See, for example, Organic Reactions, JohnWiley & Sons, Inc., New York, N.Y., vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of thePGF-type or P GE-type compounds comprises transformation of the freeacid to the corresponding silver salt, followed by interaction of thatsalt with an alkyl iodide. Examples of suitable iodides are methyliodide, ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide,and the like. The silver salts are prepared by conventional methods, forexample, by dissolving the acid in cold dilute aqueous ammonia,evaporating the excess 13 ammonia at reduced pressure, and then addingthe stoichiometric amount of silver nitrate.

The novel Formulas VIII to XIII acids (R is hydrogen) are transformed topharmacologically acceptable salts by neutralization with appropriateamounts of the corresponding inorganic or organic base, examples ofwhich correspond to the cations and amines listed above. Thesetransformations are carried out by a variety of procedures known in theart to be generally useful for the preparation of inorganic, i.e., metalor ammonium, salts, amine acid addition salts, and quaternary ammoniumsalts. The choice of procedure depends in part upon the solubilitycharacteristics of the particular salt to be prepared. In the case ofthe inorganic salts, it is usually suitable to dissolve the acid inwater containing the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt of the prostanoic acid derivative.Evaporation of the water or addition of a Water-miscible solvent ofmoderate polarity, for example, a lower alkanol or a lower alkanone,gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent ofeither moderate or low polarity. Examples of the former are ethanol,acetone, and ethyl acetate. Examples of the latter are diethyl ether andbenzene. At least a stoichiometric amount of the amine corresponding tothe desired cation is then added to that solution. If the resulting saltdoes not precipitate, it is usually obtained in solid form by additionof a miscible diluent of low polarity or by evaporation. If the amine isrelatively volatile, any excess can easily be removed by evaporation. Itis preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid with the stoichiometric amount of the corresponding quaternaryammonium hydroxide in water solution, followed by evaporation of thewater.

The invention can be more fully understood by the following examples.

Infrared absorption spectra are recorded on a Perkin- Elmer Model 421infrared spectrophotometer. Undiluted (neat) samples of the liquids andoils are used. Mineral oil (Nujol) mulls of the solids are used.

NMR spectra are recorded on a Varian A-60 spectrophotometer withtetramethylsilane as an internal standard (downfield) and using solventsas indicated below.

Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4source (ionization voltage 70 ev.).

The term oxoin front of a compound name, e.g., 15-oxo-PGF refers to aprosta-glandin analog wherein the moiety at the 15-position has beentransformed to Example 1.-15-oxoPGF solve B (a mixture of isomerichexanes). Evaporation of the eluates gives 545 mg. of 15-oxo-PGFinfrared absorption at 3400, 2660, 1700, 1660, 1620, 1460, 1410, 1375,1285, 1250, 1185, 1120, 1070, and 980 CHI-1.

Example 2.-15-oxo-PGF 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.0 g.)is added to a solution of PGF (1.3 g.) in ml. of dioxane. The mixture isstirred 24 hours at 50 C. under nitrogen, and is then cooled to 20 C.and filtered. The filtered solids are washed with dichloromethane.Evaporation of the combined filtrate and washings at reduced pressuregives 1.6 g. of a residue which is chromatographed on 400 g. of silicagel (Silicar CC-4; Mallincrodt), eluting with 75% ethyl acetate inSkellysolve B. Evaporation of the eluates gives 1.15 g. of 15-oxo-PGFinfrared absorption at 3380, 2660, 1720, 1705, 1665, 1620, 1460, 1405,1370, 1325, 1285, 1235, 1190, 1080, 1040, and 980 crnr Example3.-15-oxo-PGF Following the procedure of Example 1, PGF is oxidized to15-oxo-PGF infrared absorption at 3400, 2660, 1705, 1 660, 1625, 1405,1375, 1320, 1290, 1245-1225, 1215-1175, 1115, 1075, 1050, and 980 cm.-

Example 4.15-oxo-PGF Following the procedure of Example 1, PGF isoxidized to l5-oxo-PGF infrared absorption at 3380, 3010, 2650, 1705,1655, 1625, 1320, 1295, 1245-1225, 1190, 1085, 1040, and 980 cm.

Following the procedure of Example oxidized to 15-oxo-PGF Example6.15-oxo-PGF Example 7.Dihydro-15-oxo-PGF Following the procedure ofArkiv for Kemi, 25, 293 (1966), dihydro-PGF is oxidized todihydro-lS-oxo- PC11 with the 15-hydroxyprostaglandin dehydrogenaseenzyme of swine lung.

Following the procedure of Example 7, dihydro-PGF is oxidized todihydro-lS-oxo-PGF Also following the procedure of Example 7, themethyl, ethyl, tert-butyl, and 2-ethylhexyl esters of dihydro-PGF anddihydro-PGF are each oxidized to the corresponding 15 oxo compounds.

Also following the procedure of Example 7, the racemic forms ofdihydro-PGF dihydro-PGF and the methyl, ethyl, tert-butyl, and2-ethylhexyl esters of each of those are each oxidized to thecorresponding racemic 15-oxo compound.

Example 8.Tris-(trimethylsilyl) derivatives of 15-oxo- I I GF 1A mixtureof hexamethyldisilazane (11 ml.) and trimethylchlorosilane (2.2 ml.) isadded to a solution of 15-oxo-PGF (545 mg.) in 55 ml. oftetrahydrofuran. This mixture is stirred 16 hours at 25 C. undernitrogen, and is then filtered. The filtrate is evaporated under reducedpressure. Xylene (50 ml.) is added to the residue and the mixture isevaporated at 60 C. under reduced pressure. This addition of xylene andevaporation is re- 1, PGF is 15 peated twice. The resulting residue isthe tris-(trimethylsilyl) derivative of 15-oxo-PGF infrared absorptionat 1365, 1250, and 1180 cm.-

Example 9.Tris-(trimethylsilyl) derivatives of 15-oxo-PGF Following theprocedure of Example 8, 1'5-oxo-PGF is transformed to thetris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680,1635, 1375, 1250, 1180, 1065, 980, 840, and 750 cm.-

Example 10.Tris-(trimethylsilyl) derivative of 15-oxo-PGF Following theprocedure of Example 8, l-oxo-PGF is transformed to thetris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680,1635, 1250, and 845 cm.

Example 11.-Tris-(trimethylsilyl) derivative of 15-oxo-PGF Following theprocedure of Example 8, l5-oxo-PGF is transformed to thetris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680,1635, 1250, and 845 cm.-

Example 12.Tris-(trirnethylsilyl) derivative of 15-oxo-PGF Following theprocedure of Example 8, 15-oxo-PGF is transformed to thetris-(trimethylsilyl) derivative.

Example 13.Tris-(trimethylsilyl) derivative of 15-oxoPGF Following theprocedure of Example 8, 15-oxo-PGF is transformed to thetris-(trimethylsilyl) derivative.

Example 14.Tris-(trimethylsilyl) derivative of dihydro-15-oxo-PGFFollowing the procedure of Example 8, dihydro-15- oxo-PGF is transformedto the tris-(trimethylsilyl) derivative.

Example 14A.-Tris-(trimethylsilyl) derivative of dihydro-15-oxo-PGFFollowing the procedure of Example 8, dihydro-IS- oxo-PGF is transpormedto the tris-(trimethylsilyl) derivative.

Following the procedure of Example 8, the methyl,

ethyl, tert-butyl, and 2-ethyl-hexyl esters of 15-oxo- PGF 15-oxo-PGF15-oxo-PGF 15-oxo-PGF 15-oxo-PGF l5-oxo PGF dihydro-15-oxo-PGF anddihydro-lS-oxo-PGF are each transformed to the correspondingbis-(trimethylsilyl) derivative.

Also following the procedure of Example racemic forms of 15-oxo-PGF15-oxo-PGF 15-oxo- PGF 15-oxo-PGF 15-oxo-PGF3. 15-oxo-PGFdihydro-15-oxo-PGF dihydro-15-oxo-PGF and the methyl, ethyl, tert-butyl,and 2-ethylhexyl esters of "each of those are each transformed totrimethylsilyl derivatives, the acids to tris derivatives and theestersto .bis

derivative. a

Also following the procedure of Example 8 but using appropriatereactants in place of the hexamethyldisilazane v,

8, the

Example 15.-15-methyl-PGF and 15-methyl- 15 (R)-PGF A 3 molar diethylether solution of methylmagnesium bromide (0.55 ml.) is added dropwiseto a stirred solution of the tris-(trimethylsilyl) derivative of15-oxo-PGF (850 mg.) in 25 ml. of diethyl ether at 25 C. The mixture isstirred 30 minutes at 25 C., after which an additional 0.2 ml. of themethylmagnesium bromide solution is added and stirring is continued anadditional 30 minutes. The resulting reaction mixture is poured into 75ml. of saturated aqueous ammonium chloride solution at 0 C. Afterstirring several minutes, the mixture is extracted repeatedly withdiethyl ether. The combined diethyl ether extracts are Washed withsaturated aqueous sodium chloride solution and then dried with anhydroussodium sulfate. Evaporation of the diethyl ether gives a yellow oil (910mg.) which is dissolved in 45 ml. of ethanol. That solution is dilutedwith 30 ml. of water, and the mixture is stirred 4 hours at 25 C. Theethanol in the resulting solution is evaporated at reduced pressure, andthe aqueous residue is saturated with sodium chloride and then extractedwith ethyl acetate. The extract is washed with saturated aqueous sodiumchloride solution, dried with anhydrous sodium sulfate, and evaporatedunder reduced pressure to give 640 mg. of a mixture of 15-methyl-PGF and15-methyl-15(R)-PGF infrared absorption at 3280, 2600, and 1710 cmr Themixture of IS-methyl-PGF and 15-methyl- 15 (R)-PGF is dissolved in 50ml. of diethyl ether and cooled to 0 C. Excess diazomethane dissolved indiethyl ether is then added, and the mixture is maintained 5 minutes at0 C. and then 5 minutes at 25 C. The solution is evaporated in a streamof nitrogen, and the residue is chromatographed on 550 g. of neutralsilica, eluting with 75% ethyl acetate in Skellysolve B. Evaporation ofeluate fractions gives, successively, 127 mg. of 15- methyl-15(R)-PGFmethyl ester, 150 mg. of a mixture of 15-methyl-15(R)-PGF methyl esterand 15-methyl- PGF methyl ester, and 228 mg. of IS-methyl-PGF methylester. The latter crystallizes on standing; M.P. 72-75 C.; mass spectralmolecular ion peaks at 366, 348, 317, 313, and 294.

Aqueous potassium hydroxide solution (45%; 0.9 ml.) is added to asolution of 15-methyl-PGF methyl ester (228 mg.) in a mixture of 6.8 ml.of methanol and 2.2 ml. of water under nitrogen. The resulting solutionis I stirred 2 hours at 25 C., and is then poured into several volumesof water. The aqueous mixture is extracted with ethyl acetate, acidifiedwith 3 N hydrochloric acid, saturated with sodium chloride, and thenextracted repeatedly with ethyl acetate. The latter ethyl acetateextracts are combined, washed successively with water and saturatedaqueous sodium chloride solution, dried with anhydrous sodium sulfate,and evaporated under reduced pressure. The crystalline residue isrecrystallized from a mixture of ethyl acetate and Skellysolve B to give15- methyl-PGF M.P. 81-83 C.; infrared absorption at 3410, 3300, 2650,1705, 1305, 1290, 1275, 1255, 1220, 1195, 1125, 1075, 980, and 915 emf-NMR peaks (dimethylformamide) at 5.5 and 4.43.6 (multiplet) 8; massspectral molecular ion peaks at 643, 587, and 568.

Following the above procedure, 15-methyl-15(R)- PGF methyl ester issaponified to 15-methyl-15(R)- P-GF infrared absorption at 3380, 2650,1710, 1460, 1410, 1375, 1275-1200, 1125, 1075, 1040, and 975 cmf NMRpeaks (dimethylformamide) at 5.50 and 4.40-3.60

. (multiplet) 5; mass spectral molecular ion peaks at 352,

334, 316, and 263.

Example 16.15-methy1-PGF and 15-methyl-15(R)- PGF A 3 molar diethylether solution of methylmagnesium bromide (0.67 ml.) is added dropwiseto a stirred solution of the tris-(trimethylsilyl) derivative of 15-oxo-PGF (910 mg.) in 25 ml. of diethyl ether at 25 C. The

mixture is stirred 30 minutes at 25 C., after which an additional 0.3ml. of methylmagnesium bromide solution is added and stirring iscontinued an additional 15 minutes. The resulting reaction mixture ispoured into a mixture of ice and 75 ml. of saturated aqueous ammoniumchloride solution. After stirring several minutes, the mixture isextracted repeatedly with diethyl ether. The combined diethyl etherextracts are washed with saturated aqueous sodium chloride solution andthen dried with anhydrous sodium sulfate. Evaporation of the diethylether at reduced pressure gives a colorless, viscous oil which isdissolved in 30 ml. of ethanol. That solution is diluted with 20 ml. ofwater, and the mixture is stirred 3 hours at 25 C. The ethanol in theresulting solution is evaporated at reduced pressure, and the aqueousresidue is diluted with an equal volume of saturated aqueous sodiumchloride solution and then extracted repeatedly with ethyl acetate. Thecombined extracts are washed with saturated aqueous sodium chloridesolution, dried with anhydrous sodium sulfate, and evaporated at reducedpressure to give 700 mg. of a crystalline mixture of 15- methyl-PGF and15-methyl-15(-R)-PG*F Recrystallization of this mixture three times fromethyl acetate containing a trace of methanol gives 15-methyl-PGF M.P.164-164.5 C.; infrared absorption at 3250, 3160, 2700, 1710, 1330, 1315,1305, 1085, 1035, and 970 cmr NMR peaks (dimethylformamide) at 5.53(doublet), 5.10-3.6 (multiplet), and 1.20 (singlet) 6; mass spectralmolecular ion peaks at 370, 352, and 334.

15-methyl-15(R)-PGF is obtained from the abovedescribedrecrystallization mother liquors.

Example 17.-15-methyl-PGF and 15-methyl-(15)- PGF Following theprocedure of Example 15, the tris-(trimethyl) derivaives of 15-oxo-PGF(500 mg.) is transformed first to a mixture of 15-methy1-PGF and 15-methyl-15(R)-PGF and then to the corresponding mixture of methyl esters.This methyl ester mixture (520 mg.) is chromatographed on 500 g. ofneutral silica gel (Merck), eluting successively with 2 l. of 20%, 6 l.of 40%, and 8 l. of 50% ethyl acetate in Skellysolve B. Thecorresponding eluates emerging from the column are discarded. Elution iscontinued successively with gradients of 4 l. of 50% and 4 l. of 60%ethyl acetate in Skellysolve B, and 5 1. of 60% and 5 l. of 75% ethylacetate in Skellylsolve B, and then with 4 1. of 75% ethyl acetate inSkellysolve B, collecting the corresponding eluates in 500-ml.fractions. Elution is further continued successively with 5 l. of 75ethyl acetate in Skellysolve B and with 6 l. of 100% ethyl acetate,collecting the corresponding eluates in 200-1111. fractions. Eluatefractions 29-35 are combined and evaporated to give 109 mg. of15-methyl-15(-R)PGF methyl ester. Eluate fractions 39-67 are combinedand evaporated to give 155 mg. of 15-methyl-PGF methyl ester.

Following the procedure of Example 15, IS-methyl- PGF methyl ester issaponified to give 15-methyl-PGF infrared absorption at 3260, 2600,1710, 1365, 1235, 1040, and 970 cmr' NMR peaks (deuterchloroform) at5.82, 5.65-5.15 (multiplet), and 4.2-3.86; mass spectral molecular ionpeaks at 350, 332, and 314.

Also following the procedure of Example 15, 15-methyl-15(R)-PGF methylester is saponified to IS-methyl- 15(R)-PGF infrared absorption at 3250,2600, 1710, 1235, 1040, and 970 cm.-' NMR peaks (deuterochloroform) at6.15 (singlet), 4.20-3.8 (multiplet), and 0.90 (triplet).

Example 18.-15-methyl-PGF and 15-methyl-15 (R)-PGF Following theprocedure of Example 15, the tris-(trimethylsilyl) derivative of15-oxo-PGF (5.1 g.) is reacted with a totalof 8 ml. of 3 molarmethylmagnesium bromide in diethyl ether, and the product is hydrolyzedto give a mixture of IS-methyl-PGF and 15-methyl-15(R)-PGF (4.37 g.) inthe form of a dark oil. Crystallization of this oil from a mixture ofmethanol and ethyl acetate, and recrystallization of the resultingcrystals from a mixture of the same solvents gives 15-methyl-PGF M.P.134- 134.5 C.; infrared absorption at 3250, 3180, 2720, 1710, 1345,1305, 1235, 1085, 1050, 970, and 920 cmr NMR peaks (dimethylsulfoxide)at 5.46 (doublet), 5.0-4.0, and 3.8 (multiplet) 6; mass spectralmolecular ion peaks at 368, 350, 332, 314, 297, 278, and 205.

15-methyl-15(R)-PGF is obtained from the mother liquors of the abovecrystallization and recrystallization of IS-methyI-PGF Example19.15-methyl-PGF and 15-methyl-15 3..

Example 20.-15-rnethyl-PGF and 15-methyl-l5 (R)-PGF Following theprocedure of Example 15, the tris(trimethylsilyl) derivative of15-oxo-PGF is reacted with methylmagnesium bromide, and the product ishydrolyzed to give a mixture of 15-methyl-PGF and 15-methyl-l5 (R)-PGFThis mixture is converted to the corresponding mixture of methyl esterswhich are separated by chromatography and saponified as described inExample 15. Alternatively, the mixture of acids is separated asdescribed in Example 16.

Example 21.-Dihydro-15-methyl-PGF and dihydro-lS- methyl- 15 (R)-PGFFollowing the procedure of Example 15, the tris-(trimethylsilyl)derivative of dihydro-15-oxo-PGF is reacted with methylmagnesiumbromide, and the product is bydrolyzed to give a mixture ofdihydro-15-methyl-PGF and dihydro15-methyl-15(R)-PGF This mixture isconverted to the corresponding mixture of methyl esters which areseparated by chromatography and saponified as described in Example 15.Alternatively, the mixture of acids is separated as described in Example16.

Example 22.Dihydro-1S-methyl-PGF and dihydro-lS- methyl-15 (R)-PGFFollowing the procedure of Example 15, the tris-(tri methylsilyl)derivative of dihydro-lS-oxo-PGF is reacted with methylmagnesiumbromide, and the product is hydrolyzed to give a mixture ofdihydro-lS-methyl-PGF and dihydro-lS-methyl-IS (R)-PGF This mixture isconverted to the corresponding mixture of methyl esters which areseparated by chromatography and saponified as described in Example 15Alternatively, the mixture of acids' is separated as described inExample 16.

Following the procedure of Example 15, the methyl, ethyl, tert-butyl,and 2-ethyl-hexyl esters of the bis-(trimethylsilyl) derivatives of15-oxo-PGF 15-oxo-PGF 15-oxo-PGF2.., 15-oxo-PGF 15-oxo-PGF 15-oxo- PGFdihydro-15-oxo-PGF and dihydro-15-oxo-PGF are each transformed to thecorresponding 15-methyl and 15-methyl-15(R) esters.

Also following the procedure of Example 15, the racemic forms of thetrimethylsilyl derivatives of 15-oxo- PGF 15-oxo-PGF 15-oxo-PGF15-oxo-PGF 15- oxo-PGF 15-oxo-PGF dihydro-15-oxo-PGF dihydro-lS-oxo-PGFand the methyl, ethyl, tert-butyl, and

2-ethylhexyl esters of .each of those, tris derivatives of.-

19 the acids and his derivatives of the esters, are each transformed tothe corresponding 15-methyl and 15-methyl-15 (R) acid or ester.

Also following the procedure of Example 15, the tris- (triphenylsilyl)and tris-(tribenzylsilyl) derivatives of 15- oxo-PGF 15-oxo-PGF15-oxo-PGF 15-oxo-PGF 15-oxo-PGF 15-oxo-PGF dihydro-IS-oxo-PGF anddihydro-l5-oxo-PGF and of the racemic forms of each of those opticallyactive acids, and also the bis-(triphenylsilyl) and bis-(tribenzylsilyl)derivatives of the corresponding methyl, ethyl, tert-butyl, and2-ethylhexyl esters of each of those optically active and racemic acidsare each transformed to the corresponding 15-methyl and 15- methyl-15(R)acid or ester.

Also following the procedure of Example 15 but using ethylmagnesiumbromide in place of the methylmagnesium bromide, thetris-(trimethylsilyl), tris-(triphenylsilyl), and thetris-(tribenzylsilyl) derivatives of 15-oxo-PGF 15-oxo-PGF 15-oxo-PGF15-oxo-PGF 15-oxo- PGF 15-oxo-PGF dihydr-15-oxo-PGF dihydro-15- oxo-PGFand the racemic forms of each of those optically active acids, and alsothe bis-(trimethylsilyl), bis- (triphenylsilyl), andbis-(tribenzylsilyl) derivatives of the methyl, ethyl, tert-butyl, and2-ethylhexyl esters of each of those optically active and racemic acidsare each transformed to the corresponding 15-ethyl and 15-ethy1-15(R)acid or ester.

Example 23.15-methyl-PGE A solution of 15-methyl-PGF (95 mg.) in 40 m1.of acetone is cooled to --10 C. Jones reagent (0.1 ml. of a solution of21 g. of chormic anhydride, 60 ml. of water, and 17 m1. of concentratedsulfuric acid (precooled to 0 C., is added with vigorous stirring. Afterminutes at C., thin layer chromatography on silica gel (aceticacidzmethanolzchloroform; 5 :5 :90) of a small portion of the reactionmixture indicates about 50% reaction completion. An additional 0.06 ml.of Jones reagent is added to the still cold reaction mixture withstirring, and the mixture is stirred an additional 5 minutes at 10 C.Isopropyl alcohol (1 ml.) is added to the cold reaction mixture. After 5minutes, the mixture is filtered through a layer of diatomaceous silica(Celite). The filtrate is evaporated at reduced pressure, and theresidue is mixed with 5 ml. of saturated aqueous sodium chloridesolution. The mixture is extracted repeatedly with ethyl acetate, andthe combined extracts are washed with saturated aqueous sodium chloridesolution, dried with anhydrous sodium sulfate, and evaporated at reducedpressure. The residue is chromatographed on 20 g. of neutral silica gel,eluting with 50% ethyl acetate in Skellysolve B. Evaporation of theeluates gives 29 mg. of -methyl-PGE mass spectral molecular ion peaks at350, 332, 317, and 261.

Example 24.15-methyl-PGE A solution of l5-methyl-PGF ,,(300 mg.) in 100ml. of acetone is cooled to --35 C. Jones reagent (0.2 ml.) is addedwith vigorous stirring, and stirring is continued for 15 minutes. Atthat point, thin layer chromatography on silica gel (aceticacid:methanolzchloroform; 5:5:90) of a small portion of the reactionmixture indicates about 75% reaction completion. An additional 0.1 ml.of Jones reagent is added to the reaction mixture and stirring iscontinued at -35 C. for a total reaction time of 45 minutes. Isopropylalcohol (1 ml.) is added to the cold reaction mixture which is thenallowed to warm to 0 C. and is filtered through Celite. The filtrate isevaporated at reduced pressure, and the residue is dissolved indichloromethane. That solution is washed with saturated aqueous sodiumchloride solution, dried with anhydrous sodium sulfate, and evaporatedat reduced pressure. Each 50 mg. of residue is chromatographed on a thinlayer plate x 20 cm.; with a 1000p layer of neutral silica gel),developing twice with the A-IX solvent system. The silica el areascontaining the desired product as shown by 20 small-scale thin layerchromatography are removed from each plate, combined, placed on top of aneutral silica gel column, and eluted through the column with 10%methanol in ethyl acetate. Evaporation of the eluate gives 15-methyl-PGEinfrared absorption at 3400, 2650, 1725, 1600, 1460, 1380, 1280,1350,1150, 1125, and 1075 cmr' mass spectral molecular ion peaks at 366,348, 330-, and 259.

Example 25.15-methyl-PGE Following the procedure of Example 24,IS-methyl- PGF is oxidized to 15methyl-PGE Example26.Dihydro-15-methyl-PGE Following the procedure of Example 24,dihydro-l5- methyl-PGE is oxidized to dihydro-15-methyl-PGE Example 27.l 5 -methyl- 1 5 (R -PGE Following the procedure of Example 24,lS-methyl- 15 (R)-PGF is oxidized to 15-methyl-15(R)-PGE Example28.l5-methyl-15 (R) -PGE Following the procedure of Example 24,l5-methyl- 15(R)-PGF is oxidized to 15-methyl-15(R)-PGE Example29.15-methyl-15(R) -PGE Following the procedure of Example 24,15-methyl- 15(R)-PGF is oxidized to 15-methyl-15(R)-PGE Example 30.Dihydro- 1 5 (R) -PGE Following the procedure of Example 24,dihydro15- methyl-15(R)-PGF is oxidized to dihydro-l5-methyl- 15(R)-PGEFollowing the procedure of Example 24, 15-methyl- PGF1,,,15-methyl-15(R)-PGF 15-methyl-PGF 15- methyl-l5(R)-PGF 15-methyl-PGF15-methyl-15(R)- PGF dihydro-15-methyl-PGF and dihydro-15-methyl-15(R)-PGF are each oxidized to the corresponding PGE compound.

Also following the procedure of Example 24, the methyl, ethyl,tert-butyl, and Z-ethyl-hexyl esters of 15- methyl PGFM 15 methyl PGF 15methyl-15(R)- PGF 15-methyl15(R)-PGF 15-methy1-PGF 15- methyl PGF 15methyl l5 (R)-PGF2, IS-methyl- 15(R)-PGF 15-methyl-PGF 15-methyl-PGF 15-methyl-15 (R) -PGF 15-methyl-15 (R)-PGF dihydro- 15-methyl-PGFdihydro-15-methyl-PGF dihydro-15- methyl 15(R) PGF and dihydrol5-methyl-l5(R)- PGF are each oxidized to the corresponding IS-methyl-PGE or l5-methyl-15(R)-PGE ester.

Also following the procedure of Example 24, the racemic forms of15-methyl-PGF 15-methyl-PGF 15- methyl-15(R)-PGF 15-methyl-15(R)-PGF15-methyl-PGF 15-methyl-PGF 15-methy1-15(R)-PGF 15- methyl 15 (R) PGF 15methyl-PGE, 15-methyl- PGF 15 methyl 15 (R) PGF3... 15-methyl-15(R)- PGEdihydro 15 methyl-PGE." dihydro-15-methyl- PGEdihydro-15-methyl-15(R)-PGF and dihydro-15- methyl-15(R)-PGF and themethyl, ethyl, tert-butyl and 2-ethylhexyl esters of each of thoseracemic acids are each oxidized to the corresponding racemicIS-methyI-PGE or l5-methyl-15(R)-PGE acid or ester.

Also following the procedure of Example 24, 15-ethyl- PGF IS-ethyI-PGF15-ethyl-15(R)-PGF 15-ethyl- 15(R)-PGF IS-ethyI-PGF 15-ethyl-PGF15-ethyl- 15 (R) PGF 15 ethyl-15 (R)-PGF 15-ethyl-PGF 15-ethyl-PGF15-ethyl-15(R)-PGF3., 15-ethyl-15(R)- PGF dihydro-15-ethyl-PGFdihydro-IS-ethyl-PGF dihydro 15-ethyl-15(R)-PGF dihydro-15-ethyl-15(R)-PGE and the racemic forms of each of those optically active acids, andthe methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of thoseoptically active and racemic acids are each oxidized to thecorresponding IS-ethyl- PGE or 15-ethy1-15(R)-PGE acid or ester.

21 22 I claim: References Cited 1. An optically active compound of theformula P 3,514,383 5/1970 Beal III et a1 260-46s'x /W 5 3,706,789 12/1972 Bergstrom et a1 260-488 000R FOREIGN PATENTS W 782,822 8/1972Belgium 260-468 5 OTHER REFERENCES 10 Corey et al., Tet. Letters, 3111970). or a racemic compound of that formula and the mirror Corey etal., JACS 91, 5675 (1969).

image thereof, wherein R is hydrogen, alkyl of one to 8 carbon atoms,inclusive, or a pharmacologically acceptable LORRAINE A. WEINBERGER,Primary Examiner cation, and wherein R is methyl or ethyl. R ERSTL 2.15-methy1-15(R) -PGF an optically active com- 5 G Asslstant Exammerpound according to claim 1 wherein R is hydrogen and C1 R is methyl.

B-VRaCemiC 2., a compound 260--211, 247.2 R, 218 R, 293.65, 326.3,424.4, 430, cording to claim 1 wherein R is hydrogen and R is 439 R, 445R, 443-8 8 D, 501.1, 501.1 S, 501.17 methyl. 20

0 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 5, h9 DATED Apri i 16, 1974 |NVENTOR(S): Gordon L. Bundy It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 2, l i ne 57, "and" should read to l i ne 59, "contai n numbersshould read contain equal numbers Column 6, line 11, "about rig." shouldread about 50 ug. Column 9, line 21,

"or X trans should read or X is trans Column 11, l i ne 3, "of" shouldread to line 22, "55 i" should read 556% line 28, "PGF should read PGFline 29, "PGF should read PGF g line 52, "Pierece" should read Pierce.Column 13, line 67, "benzoquino uine" should read benzoquinone= Column17, l i ne 5}, "15-Methyl 15 -PGF should read 15-Methyl- 15(R PGF l ines 55 36, tris (trimethyl derivai ves" should read tris-(trimethylsilyl derivative Column 18, line 66, 15 oxo-PGF g" should read 15 oxo-PGFColumn 19, l i ne 52, chormic should read chromic l ine 55, acid( shouldread acid) Column 20, line 6, "1280, 1550, 1150" should read 1280, 1250,1125 Signed and Scaled this ninth Day of September 1975 Q [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN O Arresting Officer Commissioneruj'Pulenrs and Trademarks

